HK1018203B - Improved vision through photodynamic therapy of the eye - Google Patents

Description

Improvement of vision by photodynamic therapy of the eye

Technical Field

The present invention relates to a method for improving visual acuity by applying photodynamic therapy (PDT) to the eye.

Background

Loss of visual acuity is a common problem associated with aging and various eye diseases. Particularly troublesome is the occurrence of unwanted neovascularization of the cornea, retina or choroid. In many known eye diseases (including macular degeneration, ocular histoplasmosis syndrome, myopia and inflammatory diseases), choroidal neovascularization leads to hemorrhage and fibrosis, ultimately with loss of vision. Age-related macular degeneration (AMD) is the leading cause of new blindness in the elderly, with choroidal neovascularization accounting for 80% of severe vision loss in patients with age. Although the natural history is the final regression of the quiescent and neovascularization processes, this is at the expense of subretinal fibrosis and vision loss.

Currently, treatment of AMD relies on vascular occlusion by laser photocoagulation. However, this treatment requires thermal destruction of neovascular tissue, with full-thickness retinal damage and moderate to large choroidal vascular damage. Furthermore, subjects were left with atrophic scars and visual blind spots. In addition, recurrence is common and vision prognosis is poor.

Developing strategies seek a more selective vascular closure approach to protect the overlying sensory nerve-capped retina. One such strategy is photodynamic therapy, which relies on low intensity light exposure of light sensitive tissue to produce a damaging effect. The photoactive compound is administered to reach a particular undesirable tissue, and the tissue is then irradiated with light that is absorbed by the photoactive compound. This results in damage or injury to the surrounding tissue.

Over the past decades, photodynamic therapy of ocular diseases with various photoactive compounds has been attempted: for example, porphyrin derivatives such as hematoporphyrin derivatives and Photofrin porfimer sodium; "Green porphyrins" such as benzoporphyrin derivative (BPD), MA; and phthalocyanine dyes. Schmidt, U et al describe an assay for treating Greene melanoma (a non-pigmented tumor) implanted in rabbit eyes and reaching necrosis with BPD coupled with Low Density Lipoprotein (LDL) ((IOVS(1992) 33: 1253 Abstract 2802). The abstract also describes the success of LDL-BPD in thrombogenesis on a corneal neovascularization model. Corneal tissue is distinct from retinal and choroidal tissue.

Treatment with LDL-BPD or liposomal BPDChoroidal neovascularization has been reportedIOVS(1993)34: 1303: Schmidt-Erfurth, u.etal (Abstract 2956); haiimovici, r.et al. (Abstract 2955); walsh, a.w.et. (Abstract 2954); lin, s.c.et. (Abstract 2953). Another publication is Moulton, r.s.et al. (Abstract 2294),IOVS(1993) 34：1169。

it has now been found that photodynamic treatment of eye diseases unexpectedly enhances the visual acuity of a subject.

Disclosure of The Invention

The present invention relates to a method for improving visual acuity using photodynamic therapy. This approach is particularly effective when the photodynamic therapy regimen results in a reduction in unwanted neovascularization, particularly choroidal neovascularization.

In particular, the invention relates to the use of a photoactive compound in the preparation of a medicament for improving the visual acuity of a human subject in need of photodynamic therapy. The human subject is diagnosed with one of age-related macular degeneration, other macular degeneration, ocular histoplasmosis syndrome, myopia, and inflammatory disease.

Thus, in one aspect, the invention relates to a method of enhancing visual acuity comprising administering to a subject in need of such treatment a preparation of a photoactive compound in an amount sufficient to concentrate an effective amount in the eye of the subject; allowing sufficient time to elapse to allow an effective amount of the photoactive compound to concentrate in the eye; the eye is irradiated with light absorbed by the photoactive compound.

Brief description of the drawings

FIG. 1 shows a preferred form of green porphyrin used in the method of the invention.

FIG. 2 shows the visual acuity response over time for each patient receiving PDT.

FIG. 3 shows the effect of repeated PDT on maintaining enhanced visual acuity for each patient.

Modes for carrying out the invention

In the general method forming the subject of the present invention, a subject in need of improved visual acuity is administered a suitable photoactive compound in an amount sufficient to provide an effective concentration of the intraocular photoactive compound. After a suitable time to allow an effective concentration of the compound to accumulate in the desired region of the eye, the region is irradiated with light that is absorbed by the photoactive compound. The irradiation causes excitation of the compound, which in turn causes a damaging effect on the immediately surrounding tissue. The net result is an increase in visual acuity of the subject.

Photoactive compounds

Photodynamic therapy according to the invention may be carried out with any of a number of photoactive compounds. For example, various derivatives of hematoporphyrins have been described, including improvements to hematoporphyrin derivatives, such as those described in U.S. patent nos. 5,028,621; 4,866,168, respectively; 4,649,151 and 5,438,071, the entire contents of which are incorporated herein by reference. In addition, U.S. patent nos. 5,198,460; 5,002,962 and 5,093,349 describe pheophorbide; U.S. patent nos. 5,171,741 and 5,173,504 describe bacteriochlorins; U.S. patent nos. 4,968,715 and 5,190,966 describe dimers and trimers of hematoporphyrins. The contents of these patents are also incorporated herein by reference. Also, U.S. patent No.5,079,262 describes the use of aminolevulinic acid (ALA), a precursor to hematoporphyrins, as a source of photoactive compounds, and U.S. patent No.5,166,197 describes the use of phthalocyanine photosensitizers in photodynamic therapy. The contents of all the above treatments are incorporated herein by reference. Other possible photoactive compounds include purpurins, merocyanines, and porphycenes. Particularly preferred photoactive compounds for use in the method of the invention are green porphyrins, hematoporphyrin derivatives, chlorophyll and phlorizin (phlorin). These porphyrins are described in U.S. patent nos. 4,883,790; 4,920,143, respectively; 5,095,030 and 5,171,749, the entire contents of which are incorporated herein by reference. Since these photoactive agents represent a particularly good embodiment, a typical structural formula of these compounds is shown in FIG. 1.

Referring to FIG. 1, in a preferred embodiment, R¹And R²Independently selected from C_2-6Alkoxycarbonyl, C_1-6Alkyl radical, C_6-10Arylsulfonyl, cyano and-CONR⁵CO, wherein R⁵Is C_6-10Aryl or C_1-6An alkyl group; each R³Independently of one another, is carboxy, C_2-6Alkoxycarbonyl or a salt, amide, ester or acylhydrazone thereof or is C_1-6An alkyl group; r⁴Is CH ═ CH₂OR-CH (OR)^4′)CH₃Wherein R is^4′Is H or C optionally substituted by hydrophilic substituents_1-6An alkyl group. Particularly preferred are green porphyrins of the formula shown in FIGS. 1-3 or 1-4, or mixtures thereof.

More preferred are embodiments wherein the green porphyrin is of the formula shown in FIGS. 1-3 or 1-4 or mixtures thereof, wherein R is¹And R²Independently is C_2-6An alkoxycarbonyl group; a R³Is C_2-6Alkoxycarbonyl, another R³Is C_2-6Esters of alkoxycarbonyl substituents; r⁴Is CH ═ CH or-CH (OH) CH₃。

Still further preferred are embodiments wherein the green porphyrin is of the formula shown in FIGS. 1-3, wherein R is¹And R²Is a methoxycarbonyl group; a R³is-CH₂CH₂COOCH₃Another R³Is CH₂CH₂COOH；R⁴Is CH ═ CH₂I.e., BPD-MA.

Any of the photoactive compounds described above can be used in the process of the present invention; of course, it is also possible to use mixtures of two or more photoactive compounds; however, the effectiveness of the treatment depends on the absorption of light by the photoactive compound, and therefore, if mixtures are used, compounds with similar maximum absorption are preferred.

Preparation

The photoactive agent is formulated to provide an effective concentration to a target ocular tissue. The photoactive agent can be coupled to a specific binding partner that binds to a particular surface component of the target ocular tissue, and if desired, formulated with a carrier that can deliver it to the target tissue in high concentrations. The formulation comprises the photoactive agent complexed with a low density lipoprotein.

The nature of the formulation will depend in part on the mode of administration and the nature of the photoactive agent selected. Any pharmaceutically acceptable excipient or combination thereof suitable for the particular photoactive compound may be used. Thus, the photoactive compounds may be administered in the form of an aqueous composition, a transmucosal or transdermal composition, or in an oral formulation. The formulation may also include liposomes. Particularly when the photoactive agent is a green porphyrin, the liposome composition is particularly preferred. It is believed that the liposome formulation selectively delivers the green porphyrin to the low density lipoprotein component of the plasma, which in turn acts as a carrier, delivering the active ingredient more efficiently to the desired site. With neovascularization, the number of visible LDL receptors increases and the lipoprotein phase of the green porphyrin distribution to the blood increases, appearing to be more efficiently transported to the new blood vessels. As previously mentioned, the method of the present invention is particularly effective when the patient has a loss of visual acuity with deleterious neovascularization. Green porphyrins (especially BPD-MA) interact strongly with this lipoprotein. LDL itself can be used as a carrier, but LDL is much more expensive and less used than liposome formulations. Thus, LDL (or preferably liposomes) is a better carrier for green porphyrins because green porphyrins interact strongly with liposomes and are easily entrapped in liposomes. Green porphyrin compositions comprising lipid complexes, including liposomes, are described in U.S. Pat. No.5,214,036 and U.S. patent application No.07/832,542 filed 2/5 1992, both of which are incorporated herein by reference. Liposomal BPD-MA for intravenous administration is also available from QLTP hoto therapeutics Inc., Vancouver, British Columbia.

Administration and dosage

The photoactive compounds can be administered by one of a variety of routes, such as orally, parenterally, or rectally, or the compounds can be placed directly into the eye. Parenteral administration, such as intravenous, intramuscular or subcutaneous injection, is preferred. Intravenous injection is particularly preferred.

The dosage of the photoactive compound may vary widely depending on the mode of administration, the formulation in which it is carried (e.g., in the form of liposomes), or whether it is conjugated to a target-specific ligand (e.g., an antibody or immunologically active fragment). It is generally recognized that there is a link between the type of photoactive agent, the formulation, the mode of administration, and the dosage level. It is possible to adjust these parameters to suit a particular combination.

Various photoactive compounds require different dosage ranges, with typical dosage ranges of 0.1-50mg/M if green porphyrins are used²Body surface area, preferably about 1-10mg/M²More preferably about 2-8mg/M²。

The various parameters used in the present invention for effective, selective photodynamic therapy are interrelated. Thus, the dose should be adjusted relative to other parameters, such as the luminous flux, irradiance, duration of the light used in photodynamic therapy, and the time interval between dosing and therapeutic irradiation. The use of these parameters should be adjusted to produce a significant increase in visual acuity without significant damage to the ocular tissues.

In other words, as the dose of photoactive compound is decreased, there is a tendency for the light flux required to close choroidal neovascular tissue to increase.

Light therapy

Following administration of the photoactive compound, the target tissue of the eye is irradiated at a wavelength that is absorbed by the selected drug. Spectra of the above photoactive compounds are known in the art; for any particular photoactive compound, determining the spectrum is not a trivial matter. However, for green porphyrins, the desired wavelength range is generally between about 550nm and 695 nm. Wavelengths in this range are particularly good for facilitating penetration into body tissue.

As a result of irradiation, it is believed that the photoactive compound in its excited state interacts with other compounds to form reactive intermediates, such as single bond oxygen (Singlet Qxygen), which can cause structural damage to the cell. Possible cellular targets include cell membranes, mitochondria, lysosomal membranes, and nuclei. Evidence obtained from tumor and neovascular models suggests that closure of blood vessels is the primary mechanism of photodynamic therapy, seen in epithelial cell damage, sequential platelet aggregation, degranulation and thrombosis.

The light flux in the irradiation treatment may vary widely depending on the type of tissue, the depth of the target tissue and the amount of fluid or blood thereon, but preferably varies from about 50 to 200 joules/cm²。

The irradiance typically varies at about 150-900mW/cm²At about 150-600nW/cm²Preferably, it is used. However, higher irradiance may be selected for its effectiveness and the advantage of reduced treatment time.

The optimal time between administration of the photoactive agent and the light treatment can also vary widely depending on the mode of administration, the form of administration, and the particular ocular tissue targeted. Typical times after administration of the photoactive agent range from about 1 minute to about 2 hours, preferably from about 5 to 30 minutes, more preferably from 10 to 25 minutes.

The duration of the light irradiation depends on the desired luminous flux, 600mW/cm for irradiance²The luminous flux was 50J/cm²Irradiation is carried out for 90 seconds; luminous flux of 150J/cm²In this case, the irradiation was carried out for 270 seconds.

Evaluation of treatment

Clinical trials and fundus photography typically revealed no color change immediately after photodynamic therapy, although in some cases mild retinal whitening occurred after about 24 hours. Closure of choroidal neovascularization was determined histologically by observation of endothelial cell injury. It can also be evaluated by observation of vacuolated cytoplasm and abnormal nucleus accompanying destruction of neovascular tissue.

In general, the photodynamic therapeutic effect on the reduction of neovascularization can be determined at a specific time after treatment using standard fluorescein angiography techniques.

The present invention is primarily directed to evaluating visual acuity. It is performed using standard methods in the art and conventional "eye charts" in which visual acuity is assessed by the ability to recognize letters of a certain size (typically 5 letters in a row of a given size). Determination of visual acuity is known in the art and standard methods are used to evaluate visual acuity in accordance with the present invention.

The following examples are intended to illustrate, but not limit, the present invention.

Example 1

Comparison of various PDT dyes

Patients diagnosed as suitable for experimental treatment of age-related macular degeneration (AMD) were divided into 3 groups.

Group a, 22 patients, were treated with the following protocol: administration of BPD-MA6mg/M²Body surface area, the drug was formulated in commercially available liposomal intravenous compositions available from QLT Photo therapeutics, Vancouver, BC, and administered intravenously. 30 minutes after the infusion was initiated, these patients received an irradiance of 600mW/cm from a Coherent argon dye laser No.920(Coherent Medical laser, Palo Alto, Calif.)²The total luminous flux is 50J/cm²、75J/cm²100、1J/cm²、105J/cm²Or 150J/cm²Of (e) (Ohkuma, H.et., Arch opthalmol (1983) 101: 1102-.

The second group, 15 patients, group B, like group A, also received BPD-MA6mg/M in the liposome formulation²I.v., but irradiation as described in group a started 20 minutes after infusion started.

Group C15 patients except for BPD-MA12mg/M²In addition, the same treatment protocol as group a was used.

For evaluation of patients after treatment, fluorescein angiography was performed at 1 week, 4 weeks, and 12 weeks after treatment. 3 months after treatment, visual acuity tests were performed using a standard visual acuity chart. The change in visual acuity for each group was averaged without considering the total luminous flux given.

After 3 months, patients receiving treatment regimen A showed a +0.10 improvement in visual acuity (an improvement of 1.0 indicates an improvement of one row on the conventional visual acuity chart). Patients receiving treatment regimen B showed a +0.53 improvement in visual acuity; patients receiving treatment regimen C had an average decrease in visual acuity of-0.40.

For comparison, the molecular biology analysis was performed by the Macular Photoaggregation Study Group in Clinical Sciences (1991) 109: 184 patients treated with the standard photocoagulation therapy described in 1220-. This is worse than the 179 patient samples suffering from AMD that were not treated, showing a loss of visual acuity of-2.0 over this period.

Thus, regimen B (administration of BPD6mg/M in Liposome preparations²And irradiation started after 20 minutes) was the best of these 3 protocols.

Example 2

Time course with improved visual acuity

In this study, 16 patients (after 1 week, 4 weeks and 3 months) who received regimen B as described in example 1 above were evaluated for mean visual acuity. After 1 week of treatment, the visual acuity in these patients increased on average by + 2.13; after 4 weeks of treatment, the mean was +1.25 and after 3 months was + 0.53.

These results appear to be related at least in part to the success or failure of the occlusion of Choroidal Neovascularization (CNV). Those patients of treatment regimen B, 10 of 16 patients tested with fluorescein angiography showed more than 50% CNV occlusion after 4 weeks, with a corresponding increase in visual acuity of + 1.6. After 4 weeks, CNV occlusion was shown to be less than 50% in the remaining 6 patients, with a +0.7 improvement in visual acuity.

Of the 15 patients who received regimen C of example 1,7 showed CNV blockages of greater than 50%, with an improvement in visual acuity of + 1.4. 3 out of 15 showed less than 50% CNV occlusion and a loss of visual acuity of-0.3. 5 of 15 showed typical CNV recurrence and loss of visual acuity-1.6.

On the other hand, after 4 weeks of treatment according to regimen A, 9 of 21 patients showed CNV occlusion greater than 50%, but visual acuity decreased by-0.2. 9 out of 21 showed less than 50% CNV occlusion, but the visual acuity increased by + 0.9. 3 of the 21 patients receiving treatment showed typical CNV recurrence, but visual acuity was unchanged.

After 3 months, the results are shown in table 1, in which changes in visual acuity are noted.

TABLE 1

	Treatment protocol A	Treatment regimen B	Treatment regimen C
				Typical CNV > 50% closure	+0.7(3/20)	+3(4/13)	(0/12)
Typical CNV < 50% blocking	+0.14(7/20)	0(3/13)	+1.75(4/12)
				Classic recurrence of CNV	-0.1(10/20)	-0.3(6/13)	-1.4(8/12)

Thus, there appears to be some but not complete correlation between CNV occlusion and improvement in visual acuity. The method of the invention can be most easily administered to patients with unwanted neovascularization, particularly in the choroid. Thus, suitable indications include macular degeneration, ocular histoplasmosis syndrome, myopia and inflammatory diseases.

Figure 2 is a time course of visual acuity change for each patient receiving treatment regimen B. All patients improved, but in some cases the improvement subsided over time after treatment.

Example 3

Effects of repeat therapy

Each patient was treated with treatment regimen B, as described in example 1, and then repeated treatments at 2 and 6 weeks from initial treatment. Repeated treatments appear to increase the degree of visual acuity increase the results are summarized in figure 3.

As shown in fig. 3, for example, patient No.901, starting at baseline of 20/126, had an increase in visual acuity of +2 after 2 weeks; 2 weeks after the second treatment, the increase exceeded baseline + 5. For patient 906, after the first treatment, increased by +2 at week 2; after 1 week of the second treatment, it increased to + 3. Some patients have mild relapses, and in general, repeated treatments maintain or increase visual acuity improvement.

Claims (12)

1. Use of a photoactive compound for the preparation of a medicament for improving the visual acuity of a human subject in need of photodynamic therapy.

2. The use of claim 1, wherein the eye of the subject contains unwanted neovasculature.

3. The use of claim 2, wherein the neovascularization is choroidal neovascularization.

4. Use according to claim 1, wherein the photoactive agent is a green porphyrin, a hematoporphyrin derivative, a chlorophyll and a phlorizoic acid.

5. Use according to claim 4, wherein the photoactive compound is a green porphyrin.

6. The use of claim 5, wherein the green porphyrin is a compound of the formulaWherein R is¹And R²Independently selected from C_2-6Alkoxycarbonyl, C_1-6Alkyl radical, C_6-10Arylsulfonyl, cyano and-CONR⁵CO, wherein R⁵Is C_6-10Aryl or C_1-6An alkyl group;

each R³Independently of the other is carboxy, C_2-6Alkoxycarbonyl or a salt, amide, ester or acylhydrazone thereof or is C_1-6An alkyl group;

R⁴is CH ═ CH₂OR-CH (OR)^4’)CH₃Wherein OR is^4’Is H or C optionally substituted by hydrophilic substituents_1-6An alkyl group.

7. The use of claim 6, wherein the green porphyrin is a compound of the formulaWherein R is¹Or R²Independently is C_2-6An alkoxycarbonyl group;

a R³Is C_2-6Alkoxycarbonyl, another R³Is C_2-6Esters of alkoxycarbonyl substituents; r⁴Is CH ═ CH₂or-CH (OH) CH₃。

8. The use of claim 7, wherein the green porphyrin is a compound of the formulaWherein R is¹And R²Is a methoxycarbonyl group;

a R³is-CH₂CH₂COOCH₃Another R³Is CH₂CH₂COOH；

R⁴Is CH ═ CH₂I.e., BPD-MA.

9. The use of claim 1, wherein the formulation comprises the photoactive agent complexed with a low density lipoprotein.

10. The use of claim 1, wherein the formulation is a liposomal formulation.

11. The use of claim 1, wherein the human subject is diagnosed with one of age-related macular degeneration, other macular degeneration, ocular histoplasmosis syndrome, myopia, and inflammatory disease.

12. The use of claim 1, wherein the medicament comprises the photoactive agent coupled to a specific binding ligand that binds to a target ocular tissue.